1. Field of the Invention (Technical Field)
The present invention relates to peptides and pharmaceutical compositions including peptides for the treatment of sexual dysfunction in mammals, including both male erectile dysfunction and female sexual dysfunction in humans, including methods and formulations for the use and administration of the same.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-à-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Sexual dysfunction, including both penile erectile dysfunction or impotence and female sexual dysfunction, is a common medical problem. Significant effort has been devoted over the last twenty or more years to develop methods, devices and compounds for treatment of sexual dysfunction. While more effort has been undertaken for treatment of penile erectile dysfunction, female sexual dysfunction is also an area to which significant research and effort has been devoted.
At present, one commonly used orally administered drug for treatment of sexual dysfunction in the male is Viagra®, a brand of sildenafil, which is a phosphodiesterase 5 (PDE-5) inhibitor. PDE-5 inhibitors increase the persistence of cyclic guanosine monophosphate and thereby enhance erectile response. Another drug approved in Europe for treating male erectile dysfunction is Ixense®, a brand of apomorphin that is a non-selective dopa receptor agonist. Oral and nasal formulations of apomorphin are currently undergoing clinical evaluations in the United States. There are several other medical treatment alternatives currently available depending on the nature and cause of the impotence problem. Some men have abnormally low levels of the male hormone testosterone, and treatment with testosterone injections or pills may be beneficial. However, comparatively few impotent men have low testosterone levels. For many forms of erectile dysfunction, treatment may be undertaken with drugs injected directly into the penis, including drugs such as papaverin, prostaglandin E1, phenoxybenzamine or phentolamine. These all work primarily by dilating the arterial blood vessels and decreasing the venous drainage. Urethral inserts, such as with suppositories containing prostaglandin, may also be employed. In addition, a variety of mechanical aids are employed, including constriction devices and penile implants.
A variety of treatments have also been explored for female sexual dysfunction, including use of sildenafil, although the Food and Drug Administration has not specifically approved such use. Testosterone propionate and various estrogen-related compounds have also been employed to increase or augment female libido.
A number of other agents have been shown to induce or facilitate penile erection in laboratory animals. These include very diverse classes of ligands such as oxytocin (Benelli A, Poggioli R, Luppi P, Ruini L, Bertolini A, Arletti R., Oxytocin enhances, and oxytocin antagonism decreases, sexual receptivity in intact female rats. Neuropeptides 27:245-50 (1994)), vasopressin, vasoactive intestinal peptide, melanotropins, and ACTH as well as their analogs.
It is well known to those skilled in the art of developing new therapeutic treatments for sexual dysfunction that identification of a new class of therapeutic agents is often achieved by chance. For example, investigations of sildenafil as an agent for treating high blood pressure in humans revealed its effects on facilitating penile erection in men. Similarly, clinical use of apomorphin for treatment of Parkinson's disease uncovered its effects in eliciting penile erections. Human studies on a potent melanotropin agonist as an agent to induce human skin pigmentation established its erectogenic activity. However, the mechanism by which these agents elicit a sexual activity response remains largely unknown. Some understanding of the PDE-5 class of compounds (e.g. sildenafil) has now been developed. The biological mechanism(s) by which presumably centrally acting molecules, such as oxytocin, vasopressin, apomorphin, vasoactive intestinal peptide, melanotropins and ACTH, elicit a sexual function response is still unclear. That at least a portion of the biological mechanism is central is generally understood to be demonstrated by efficacy following intracerebroventricular (ICV) administration. It is conceivable that some or all of these agents may be interacting at more than one individual receptor site involved in a common downstream biological pathway.
Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic α-melanocyte-stimulating hormone (“α-MSH”) analog, called Melanotan-II, was evaluated for erectogenic properties for treatment of men with psychogenic erectile dysfunction. Wessells H. et al., J Urology 160:389-393 (1998); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitled Compositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled Stimulating Sexual Response in Females. A related compound is claimed in U.S. Pat. No. 6,579,968, Compositions and Methods for Treatment of Sexual Dysfunction, issued Jun. 17, 2003, to C. H. Blood and others, and is in clinical trials for treatment of erectile dysfunction. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of Alpha-MSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of Alpha-MSH Fragments. Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. Other peptides are disclosed in U.S. Pat. No. 6,284,735 and U.S. Published Patent Applications Nos. 2001/0056179 and 2002/0004512.
It has long been believed that erectile response to melanocortin receptor-specific compounds, and both male and female sexual response in general, was related to the central tetrapeptide sequence, His6-Phe7-Arg8-Trp9 (SEQ ID NO:1) of native α-MSH. In general, all melanocortin peptides share the same active core sequence, His-Phe-Arg-Trp (SEQ ID NO:1), including melanotropin neuropeptides and adrenocorticotropin. MC3-R (the melanocortin-3 receptor) has the highest expression in the arcuate nucleus of the hypothalamus, while MC4-R (the melanocortin-4 receptor) is more widely expressed in the thalamus, hypothalamus and hippocampus. A central nervous system mechanism for melanocortins in the induction of penile erection has been suggested by experiments demonstrating penile erection resulting from central intracerebroventricular administration of melanocortins in rats. While the mechanism of His-Phe-Arg-Trp (SEQ ID NO:1) induction of erectile response has never been fully elucidated, it has been generally accepted that the response involves the central nervous system, and binding to MC3-R and/or MC4-R, and according to most researchers, MC4-R.
Non-peptides have been proposed which alter or regulate the activity of one or more melanocortin receptors. For example, International Patent Application No. PCT/US99/09216, entitled Isoquinoline Compound Melanocortin Receptor Ligands and Methods of Using Same, discloses two compounds that induce penile erections in rats. However, these compounds were administered by injection at doses of 1.8 mg/kg and 3.6 mg/kg, respectively, and at least one compound resulted in observable side effects, including yawning and stretching. Other melanocortin receptor-specific compounds with claimed application for treatment of sexual dysfunction are disclosed in International Patent Application No. PCT/US99/13252, entitled Spiropiperidine Derivatives as Melanocortin Receptor Agonists. International Patent Application Nos. PCT/US00/14930, PCT/US00/19408, WO 01/05401, WO/00/53148, WO 01/00224, WO 00/74679, WO 01/10842 and the like disclose other compounds that may be so utilized.
Most investigators, including those who are inventors of the above-described patents and applications, ascribe the sexual activity of melanotropin ligands to MC4-R. Evidence in favor of this hypothesis comes from the observation that a sexual response elicited by an MC4-R agonist can be blocked by an MC4-R antagonist. However, a few reports also suggest that MC4-R receptors may not be involved in eliciting sexual function response (Vergoni, A. V.; Bertolini, A.; Guidetti, G.; Karefilakis, V.; Filaferro, M.; Wikberg, J. E.; Schioth, H. B., Chronic melanocortin 4 receptor blockage causes obesity without influencing sexual behavior in male rats. J Endocrinol 166:419-26 (2000)).